The present invention relates to 3-chloro-4-halo-1,2,5-thiadiazole compounds and a method of producing novel mono- and di-substituted-1,2,5-thiadiazoles therefrom.
Since the discovery of 2,1,3-benzothiadiazole by Hinsberg in 1889 [1], chemists have shown an increasing interest in the chemistry of 1,2,5-thiadiazoles and 1,2,5-selenadiazoles.
Various compounds comprising a heteroaromatic ring of the 1,2,5-thiadiazole type present interesting properties in the pharmaceutical or agrochemical industry, and in the field of polymers. Thus, several molecules have been shown to have antibiotic [2], antihistamine [3], xcex2-adrenergic [4] and anticholingergic activities [5], as well as inhibitory activities on HIV-1 transcriptase [6]. Other thiadiazoles are active as a fungicide [7], bactericide [8], herbicide [9], growth regulator [10], insecticide [11], coccidiostatic agent [12] or antihelmetic agent [13]. Finally, the 1,2,5-thiadiazole ring has also been incorporated in several polymers presenting, among other properties, high thermal and chemical stabilities [14].
The various syntheses of 1,2,5-thiadiazoles, largely developed during the ""60s, can be grouped as a function of the precursor fragments used to construct the thiadiazole ring. The following approaches have been developed:
cyclization of an Nxe2x80x94Cxe2x80x94Cxe2x80x94N fragment by a derivative S: [4+1] approach
cyclization of a Cxe2x80x94C fragment with a derivative Nxe2x80x94Sxe2x80x94N: [3+2] approach (type A), and
cyclization of a Cxe2x80x94Cxe2x80x94N fragment by a derivative Sxe2x80x94N: [3+2] approach (type B).
The [4+1] approaches use the cyclization with sodium mono- or dichloride of compounds of the following types: xcex1-aminoacetonitrile, xcex1-dioxime, xcex1-diamine, xcex1aminoamide, xcex1-cyanoimidate and xcex1-cyanoamide. This approach was largely developed by Weinstock [15] during the 1950s.
xcex1-aminoacetonitriles are prepared from aldehydes via a Strecker reaction: 
xcex1-dioximes, prepared from 1,2-diketone precursors and xcex1-diamines lead to dialkyl- and diarylthiadiazoles: 
xcex1-aminoamides, derived from amino acids, lead to hydroxylated thiadiazoles, which can be converted to halogenated thiadiazoles by treatment with phosphorus oxychloride or oxybromide [16]
Cyanogen, the precursor of xcex1-cyanoamides and xcex1-cyanoimidates, allows the production of 3-chloro-4-hydroxylated, 3-chloro-4-alkoxylated and 3,4-dichlorinated derivatives. 
The syntheses of type [3+2] can be divided into two subclasses depending on whether the carbon fragment is of the Cxe2x80x94Cxe2x80x94N or Cxe2x80x94C type. The first subclass ([3+2] type B) involves primarily the reaction of benzyl ketones, the corresponding oximes or the xcex1,xcex1-diahalogenoketoximes with derivatives of the sulfur diimide or tetranitride type in the cyclization step. Such an approach was applied to the preparation of numerous 3-chloro- and 3-bromo-4-aryl-1,2,5-thiadiazoles with excellent yields [17]. 
The second subclass ([3+2] type A) primarily uses disubstituted acetylene derivatives, as shown below (eq. 6): 
where R and Rxe2x80x2 are aryl, alkyl, CO2R or CN.
Unfortunately, all of the standard methods for construction of the 1,2,5-thiadiazole ring have various drawbacks when applied to large-scale syntheses, including:
unavailability of cyanogen and certain other precursors,
lengthy syntheses often leading to modest overall yields,
use of very toxic, corrosive and sometimes explosive reagents (for example: S4N4 [18]), and
production of sulfur or its derivatives in the cyclization step, making purification difficult.
Alternate synthetic pathways, which are more general and allow the production of 3-chloro-4-alkyl- and 3-chloro-4-arylthiadiazoles, are therefore desirable. One of the fundamental methods of creating a carbon-carbon bond between a halogenated heterocycle and an aliphatic or aromatic group is the coupling reaction catalyzed by transition metals, as illustrated below: 
where R and Rxe2x80x2 are aryl, alkenyl, alkynyl, or alkyl; M is Li, Mg, Zn, Cu, Al, Si, Sn, or B and Mxe2x80x2 is Pd or Ni. The application of transition metal chemistry for the production of various heterocyclic ring systems is known.
In 1972, Kumada [19] and Corriu [20] independently reported that the reaction between Grignard reagents and alkyl or aryl halides can be effectively catalyzed by nickel complexes. Murahashi [21] later published the first example of catalysis with palladium using the same reaction. Extraordinary advances in the field of coupling reactions catalyzed by transition metals followed with the use of derivatives of zinc, aluminum and zirconium [22], lithium [23], copper [24], silicon [25], tin [26] and boron [27].
Palladium catalysis has been applied to form numerous xcfx80-deficient heterocycles such as pyridine, pyrimidine and pyrazines [28]. However, palladium catalysis infrequently has been applied to other heterocyclic systems, including 1,2,5-thiadiazoles. A few recent publications reported the synthesis of 3,4-diaryl-1,2,5-thiadiazoles by reacting 3-bromo- or 3-trifluoromethanesulfonyl-4-aryl-1,2,5-thiadiazoles and arylstannanes ([29], JP 10025284 A2 980127, and JP 05163258 A2 930629). 
When applied to the more readily available 3-chloro analogs, the above approach was unproductive. That is, the reaction with 3-chloro-4-phenyl-1,2,5-thiadiazole and tributyl(4-chlorophenyl)stannane led to the diarylated derivative with a yield of only 37%.
Thus, despite these recent advances, novel methods of producing 1,2,5-thiadiazoles with broader applicability for various substituents are desirable.
The present invention provides a method of synthesizing 3-chloro-4-substituted derivatives by reacting 3-chloro-4-halo-1,2,5-thiadiazoles with an organostannane or organ oborane in the presence of a catalytic amount of palladium (eq 9): 
where X is chloro, bromo, or iodo; and
RM is an organometallic group such as an organostannane or an organoborane (where R is an alkyl, alkenyl, alkynyl, aryl, or heteroaromatic group)
The present invention also provides a method of synthesizing novel 3,4-disubstituted-1,2,5-thiadiazoles from previously unknown 3-chloro-4-substituted-1,2,5-thiadiazoles by a further palladium-catalyzed cross-coupling reaction (eq 10): 
where R is as defined above; and
Rxe2x80x2M is an organometallic group such as an organostannane or an organoborane (where Rxe2x80x2 is an alkyl, alkynyl, vinyl, allyl, aryl, or heteroaromatic group or is xe2x80x94OR5, xe2x80x94SR5 or xe2x80x94NR5R6)
In the above formulae, R and Rxe2x80x2 may be unsubstituted or substituted one to three times with a substituent selected from the group consisting of alkyl, alkenyls, alkynyls, halogen, hydroxy, oxo, phosphoryl, thiol, sulfinyl, sulfonyl, aryl, heterocyclic, amine, imine, nitro, cyano, amidino, carbonyl; wherein the moieties substituted on the hydrocarbon chain can themselves be substituted with one to three further substituents.
The present invention provides novel 3-chloro-4-substituted-1,2,5-thiadiazoles of the formula (1): 
where R is xe2x80x94CR1xe2x95x90CR2R3 or xe2x80x94Cxe2x89xa1CR4;
R1 is hydrogen, alkyl, xe2x80x94OR5, xe2x80x94SR5 or xe2x80x94NR5R6;
R2 and R3 are each, independently, hydrogen, fluorine, alkyl, nitriles, O-protected alcohols, S-protected thiol, N-protected amine, CO-protected aldehydes, esters, alkylaryl and phosphine,
R4 is alkyl, aryl, or a C-protecting group (such as trimethylsilyl (TMS) or t-butyl-dimethylsilyl (TBS)); and
R5 and R6 are each, independently, a protecting group, alkyl, alkenyl, alkynyl, aryl, heterocyclic or heteroaromatic group or where R5 and R6 together with the N which they substitute, form a heteroaromatic or heteroaromatic group.
The present invention also provides novel thiadiazole compounds of the formula: 
where X is iodo (2) or bromo (3).
xe2x80x9cAlcoholsxe2x80x9d include groups of the formula xe2x80x94OH and xe2x80x94OP, where P is a O-protecting group such as Boc.
xe2x80x9cAldehydesxe2x80x9d include groups of the formula xe2x80x94C(xe2x95x90O)H.
xe2x80x9cAlkenylxe2x80x9d means a substituted or unsubstituted, straight or branched, unsaturated hydrocarbon chain that contains at least one double bond and 2 to 20, preferably 2 to 6, carbon atoms. Allyl groups, xe2x80x94CH2CHxe2x95x90CH2, and vinyl groups, xe2x80x94CHxe2x95x90CH2, are exemplary alkenyl groups.
xe2x80x9cAlkoxyxe2x80x9d means an xe2x80x94O-alkyl group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, etc.
xe2x80x9cAlkylxe2x80x9d means a substituted or unsubstituted, straight, branched or cyclic saturated hydrocarbon chain that contains 1 to 20, preferably 1 to 6, carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
xe2x80x9cAlkylarylxe2x80x9d means a C1-4 alkyl group bearing one or more aryl groups. Representatives of this group include benzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl (such as p-chlorobenzyl, p-bromobenzyl, p-iodobenzyl), 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 2-methyl-2-phenylpropyl, (2,6-dichlorophenyl)methyl, bis(2,6-dichlorophenyl)methyl, (4-hydroxyphenyl)methyl, (2,4-dinitrophenyl)methyl, diphenylmethyl, triphenylmethyl, (p-methoxyphenyl)-diphenylmethyl, bis(p-methoxyphenyl)methyl, bis(2-nitrophenyl)methyl, and the like. xe2x80x9cAlkynylxe2x80x9d means a substituted or unsubstituted, straight or branched, unsaturated hydrocarbon that contains at least one triple bond and 2 to 20, preferably 2 to 6, carbon atoms.
xe2x80x9cAminexe2x80x9d means a primary, secondary or tertiary amine. Suitable amines are of the formula xe2x80x94NH2, xe2x80x94NHR, or xe2x80x94NR2, where each R is independently an alkyl group. Exemplary amines include methylamine, dimethylamine, methylethylamine, isopropylamine, etc.
xe2x80x9cArylxe2x80x9d means or xe2x80x9caromaticxe2x80x9d means a substituted or unsubstituted, mono- or bicyclic carbocyclic aromatic ring, preferably containing 6 to 10 carbon atoms. Examples include phenyl (Ph) or naphthyl.
xe2x80x9cEstersxe2x80x9d include groups of the formula xe2x80x94C(xe2x95x90O)OR, where R is an alkyl group. Exemplary groups include methyl ester, ethyl ester, etc.
xe2x80x9cHalogenxe2x80x9d means chlorine, bromine, iodine, or fluorine.
xe2x80x9cHeteroaromaticxe2x80x9d means a 5-10 membered, substituted or unsubstituted mono-, bi- or tricyclic aromatic group wherein one or more members of the aromatic ring is a heteroatom, preferably oxygen, nitrogen or sulfur. Examples include benzofuran, benzothiophene, furan, imidazole, indole, isothiazole, oxazole, piperazine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, thiazole, and thiophene.
xe2x80x9cHeterocyclicxe2x80x9d means a 5-10 membered, substituted or unsubstituted cyclic hydrocarbon ring wherein one or more members of the ring is a heteroatom, preferably oxygen, nitrogen or sulfur. Examples include morpholino and piperazino.
xe2x80x9cIminexe2x80x9d includes groups of the formula xe2x80x94Cxe2x95x90Nxe2x80x94H or xe2x80x94Cxe2x95x90Nxe2x80x94R, where R is alkyl.
xe2x80x9cNitrilesxe2x80x9d include groups of the formula xe2x80x94Cxe2x89xa1N.
xe2x80x9cProtecting groupxe2x80x9d means a group used to protect a heteroatom such as oxygen, nitrogen, sulfur or phosphorus from chemical reaction. For example, a O-protecting group is used to protect an oxygen heteroatom, such as in a hydroxy group, from reaction. Suitable O-protecting groups include t-butyl ether, benzyl ethers, etc. Protecting groups are well known in the art, see for example Greene, T. W. Protective Groups in Organic Synthesis, John Wiley and Sons, Inc: New York. 1991. Preferred protecting groups include, but are not limited to, the xe2x80x9cBocxe2x80x9d protecting group, trialkyl silyl groups such as TBS (tert-butyldimethylsilyl, Si(CH3)2C(CH3)3), MEM, MOM, SEM, and THP.
xe2x80x9cSubstitutedxe2x80x9d means that the moiety contains at least one, preferably 1-3 substituent(s). These substituents can optionally be further substituted with 1-3 substituents. Examples of substituted substituents include carboxamide, alkylmercapto, alkylsulphonyl, alkylamino, dialkylamino, carboxylate, alkoxycarbonyl, alkylaryl, aralkyl, alkylheterocyclic ring, etc. Suitable substituents include hydrogen, hydroxyl, amino, oxy, carbonyl, thiol, alkyl, alkenyl, alkynyl, alkoxy, halo, nitrile, nitro, aryl and heterocyclic ring.
xe2x80x9cThiolsxe2x80x9d include compounds of the formula xe2x80x94SH or xe2x80x94SR where R is alkyl. Exemplary thiols include methanethiol, ethanethiol, propanethiol, etc.
The present invention also provides novel 3-chloro-4-substituted-1,2,5-thiadiazoles of the formula (1): 
where R is as defined above.
Representative new compounds include: 
which are:
3-chloro-4-(furan-2-yl)-1,2,5-thiadiazole,
3-chloro-4-(1-ethoxyvinyl)-1,2,5-thiadiazole,
3-chloro-4-vinyl-1,2,5-thiadiazole,
3-chloro-4-allyl-1,2,5-thiadiazole, and
3-chloro-4-phenylethynyl-1,2,5-thiadiazole, respectively.
Novel compounds of the formula (1) can be prepared from 3-chloro-4-(chloro-, bromo- or iodo-)-1,2,5-thiadiazoles as described below using palladium-catalyzed cross-coupling chemistry.
The present invention also provides novel 3,4-disubstituted-1,2,5-thiadiazoles of the formula (4): 
where R is as defined above; and
Rxe2x80x2 is alkyl, alkenyl, alkynyl, aryl or heteroaromatic or xe2x80x94OR9, xe2x80x94SR9, or xe2x80x94NR9R10, where R9 and R10 are each, independently, alkyl, alkenyl, alkynyl, aryl, heterocyclic or heteroaromatic group or where R9 and R10 together with the N which they substitute, form a heterocyclic or heteroaromatic group.
When Rxe2x80x2 is alkenyl, alkynyl, aryl or heteroaromatic, compounds of the formula (4) can be formed from 3-chloro-4-substituted-1,2,5-thiadiazoles (1) and an organostannane or an organoborane in a second palladium catalyzed cross-coupling reaction under the conditions described above (see also JP 10025284 A2 980127 and JP 05163258 A2 930629). It is possible to first hydrolyze the 3-chloro group to a 3-hydroxy derivative (Robey and Ward, PCT Publication No. WO96/3843 1) and subsequently brominate the same (Hanasaki, Heterocycles, 1996, 43(11): 2435) to form a 3-bromo-4-substituted-1,2,5-thiadiazoles (see eq 11 below). This intermediate is more reactive to palladium catalyzed cross-coupling than the 3-chloro derivative.
When Rxe2x80x2 is alkyl, compounds of the formula (4) can be formed from 3-chloro-, 3-bromo-, or 3-iodo-4-substituted-1,2,5-thiadiazoles and an organostannane or an organoborane in a second palladium catalyzed cross-coupling reaction under the conditions described above. 3-bromo-4-substituted-1,2,5-thiadiazoles is preferably used. 3-bromo-4-substituted-1,2,5-thiadiazoles can be formed from 3-chloro-4-substituted-1,2,5-thiadiazoles by hydrolysis to the 3-hydroxy-derivative and subsequent bromination. The overall reaction is shown below (eq 11): 
where M is, for example, xe2x80x94B(OH)2, xe2x80x94BEt2, xe2x80x94SnBu3.
When Rxe2x80x2 is xe2x80x94OR9, xe2x80x94SR9, or xe2x80x94NR9R10, compounds of the formula (4) can be formed from 3-chloro-4-substituted-1,2,5-thiadiazoles (1) by using all conventional methods reported in the literature. Alternatively, when Rxe2x80x2 is xe2x80x94OR9, xe2x80x94SR9, or xe2x80x94NR9R10, the Rxe2x80x2 group can be first introduced using methods known in the art and R can subsequently be added via a cross-coupling reaction as described above (eq 12): 
It should be understood that when Rxe2x80x2 is introduced first, if R is alkyl, then it is preferable to hydrolyze the chlorine, brominate, and then conduct the cross-coupling as shown above in eq (11).
Novel compounds of the formula: 
where X is iodo (2) or bromo (3) can be prepared by reacting an alkyl nitrite, copper(I)halide or copper(II) halide, and 3-amino-4-chloro-1,2,5-thiadiazole (5) in solution, using the methods described by Doyle et al., J. Org. Chem., vol. 42, p. 2426, 1977. 
The 3-amino-4-chloro-1,2,5-thiadiazole has been previously prepared in 44% overall yield as described by Weinstock et al., J. Org. Chem., 2823, 1967; Lentia, DE 1175683, 1962; and Oesterreich Stickstoffwerke, BE 629551, 1963.
The method of the present invention involves coupling 3-chloro-4-halo-1,2,5-thiadiazole with an organometallic group in the presence of a palladium catalyst (eq 9): 
where X is a halogen and RM is an organometallic complex where R is alkyl, alkynyl, vinyl, allyl, aryl, or heteroaromatic group.
In general, the organometallic complex and the palladium(0) catalyst are added to a solution of the 1,2,5-thiadiazole in solvent and are heated at reflux for 20-24 hours. The organometallic complex and the 1,2,5-thiadiazole are used in approximately equal molar ratio, preferably from about 1:1 to 1:0.95, respectively. A catalytic amount of palladium is used initially; however, further amounts of palladium(0) catalyst can optionally be added during the reaction.
Suitable solvents have boiling points greater than 100xc2x0 C. and are either monophasic or diphasic. Preferred solvents include toluene, dioxane, dimethoxyethane (dme), water and mixtures thereof.
Suitable palladium(0) catalysts include any tetrasubstituted palladium(0) catalyst. Some of these palladium(0) catalysts are commercially available. Preferably, tetrakistriphenyl-phosphine palladium (0) ((PPh3)4Pd) is used.
Suitable organometallic compounds are organostannanes (such as described by Stille, Angew. Chem. Int. Ed. Eng., vol. 25, p. 508 (1986) [26]) and organoboranes (such as described by Miyaura and Suzuki, Chem. Rev., vol. 95, p. 2457, 1995 [27b]). When 3,4-dichloro-1,2,5-thiadiazole is used as starting material, organostannanes are preferably used.
Suitable organostannanes include RSn(alkyl)3, such as RSnBut3 and RSnMe3, where R is as described above. RSnMe3 is preferably used, as its by-products are soluble in water. However, many RSnBut3 compounds are commercially available.
Suitable borane derivatives are described therein and include RB(OH)2, RB(alkyl)2 (such as RB(Et)2) and RB(alkoxy)2, where R is as described above. Most preferably, the borane has the general formula RB(OH)2. When an organoborane is used, the reaction mixture further comprises a base, preferably an alkaline- or alkaline-earth metal base such as K2CO3, KF, CsF, Cs2CO3, Na2CO3. Due to the presence of the base, the solvent is preferably a bi-phasic organic/water mixture. However, a monophasic organic mixture can also be used if a phase-transfer catalyst is included.
In general, the organometallic complex and the palladium(0) catalyst are added to a solution of the 1,2,5-thiadiazole in solvent and are heated at reflux. When the halogen is bromine, the reaction is conducted for about 6-10 hours, preferably about 8 hours. When the halogen is iodine, the reaction is conducted for about 1-3 hours, preferably about 2 hours. Further amounts of palladium(0) catalyst are optionally added during the reaction. Suitable solvents have boiling points greater than 100xc2x0 C. and are either monophasic or diphasic. Preferred solvents include toluene, dioxane, dimethoxyethane (dme), water and mixtures thereof.
Suitable palladium(0) catalysts include any palladium(0) species, including commercially available Pd(PPh3)4 and Pd2(dba)3 or can be prepared in situ be reduction of Pd(II) precursors like Pd(OAc)2 or PdCl2 in the presence of phosphine.
Suitable organometallic compounds are organostannanes and organoboranes. When 3-chloro-4-(iodo- or bromo-)-1,2,5-thiadiazoles are used as starting material, organoboranes are preferably used. The use of both organometallic complexes are described above. When organostannanes are used, the reaction is preferably run in a monophasic system (particularly toluene or dioxane). When organoboranes are used, the reaction is run in a biphasic mixture (such as toluene/water), using a base such as KF.
The present invention also includes a method of cross-coupling 3-chloro-4-substituted-1,2,5-thiadiazoles with an organometallic group in the presence of a palladium(0) catalyst (eq 13): 
where R and Rxe2x80x2 are each, independently, an alkyl, alkynyl, vinyl, allyl, aryl, or heteroaromatic group, or
where R is an alkyl, alkynyl, vinyl, allyl, aryl, or heteroaromatic group and Rxe2x80x2 is xe2x80x94OR5, xe2x80x94SR5 or xe2x80x94NR5R6, (where R5 and R6 are as defined above).
As compared with previous methods (JP 10025284 and JP 05163258), the present method is more general and also makes it possible to use the much less toxic organoborane reagents. For example, when starting from 3-chloro-4-phenyl-1,2,5-thiadiazole, up to 80% yield was obtained in the synthesis of the 3,4-diphenyl-1,2,5-thiadiazole, with PhB(OH)2 and KF as base.